The current invention pertains to the fields of medicinal chemistry, pharmacology, and medicine. Further, the current invention identifies compounds which are antagonists of the xcex11-adrenergic receptor.
The sympathetic nervous system is a critical system in mammals, including humans. It""s major activity is to regulate and maintain homeostasis of a wide variety of functions throughout the body. For example, the sympathetic nervous system provides control and coordinated regulation of several major cell types, among these; smooth muscle, liver, skeletal muscle, nerve, and adipoetic cells.
As a result of the system""s effect on smooth muscle cells (constriction or dilation), the sympathetic nervous system is critical in the control (flow and pressure) of fluids in the body, such as air, blood, urine, food, waste, and the like. Similarly, system effects on hepaticytes and adipocytes have a major regulatory function on energy production and utilization. For further details on the function and effects of the sympathetic nervous system, see: xe2x80x9cGoodman and Gilman""s The Pharmacological Basis of Therapyxe2x80x9d, Eds. Gilman, A. E., Rall, T. W., Nies, A. S., and Taylor, P., 8th Ed., Pergamon Press, New York, 1990, Ch. 5, pp. 84-95.
On a molecular level, the sympathetic nervous system is primarily activated by the catecholamine neurotransmitters (primarily epinephrine and norepinephrine, and to a much lesser extent, outside the central nervous system, dopamine). For further information see: ibid., Chap. 10 and references cited therein. The action or response of a particular cell type to catecholamine stimuli is dependent on the type of receptor on that cell. Germane to the current invention, are the receptors of the sympathetic nervous system known as adrenergic receptors. Most germane to the current invention are the actions of the xcex1 receptor and more specifically the xcex11 receptor.
The xcex11 receptor is a major regulatory element on smooth muscle cells. Thus, tissues containing large numbers of these cells are often highly effected by agonist or antagonists to this receptor. Such tissues would include the arterioles, veins, sphincter, trigone, skin, male ejaculatory system, and the like. In general, activation of the xcex11 receptor causes the smooth muscle cells to contract. Thus, activation may have the effect of constricting the vasculature and raising blood pressure, constricting the urinary tract and restricting urine flow, and the like. Compounds which block the xcex11 receptor have the opposing effects, i.e., vasodilatation, etc.
Thus, xcex11 receptor antagonists are potential therapeutic agents for hypertension, congestive heart failure, and other cardiovascular diseases. Additionally, xcex11 antagonists have been used successfully in increasing urinary flow in patients suffering from benign prostatic hyperplasia (BPH), see: xe2x80x9cPharmacological Options in the Treatment of Benign Prostatic Hyperplasiaxe2x80x9d, Kenny, B., et al., J. Med. Chem., 40(9), pp. 1293-1315 (1997).
Currently, the most widely used compounds which block the xcex11 receptor are a series of piperazinyl quinazolines, e.g., prazosin, terazosin, doxazosin, and trimazosin. Of these, the most commonly used compound is prazosin (Minipress(trademark)). Although, this compound is quite beneficial in lowering blood pressure, it can also cause postural hypotension and syncopal episodes. (For further information, see: xe2x80x9cPhysician""s Desk Referencexe2x80x9d, 47th Ed., Medical Economics Co., Montvale N.J., 1993, pp. 1834-5). Thus, a need currently exists for new xcex11 antagonists.
The current invention relates to a method for antagonizing xcex11-adrenergic receptors which includes administering, to a mammal in need thereof, an effective amount of a compound of formula I: 
or an N-oxide or pharmaceutical salt or solvate thereof; wherein A is a moiety selected from the group consisting of: 
wherein:
R and R1 are independently hydrogen, hydroxy, chloro, bromo, C1-C4 alkyl, C1-C4 alkoxy, OCOC1-C6 alkyl, OCO(phenyl), or OCO(substituted phenyl);
X is oxygen or sulfur; and
Y is oxygen, CH2, or CO.
The present invention further relates to a method of inhibiting the pathological states or sequelae resulting from inappropriate activation of xcex11-adrenergic receptors comprising administering, to a mammal in need thereof, an effective amount of a compound of formula I.
Moreover, the present invention relates to the use of a compound of formula I for the manufacture of a medicament useful as an antagonist of the xcex11-adrenergic receptor.
In addition, the present invention relates to the use of a compound of formula I for the manufacture of a medicament for the inhibition of pathological states or sequelae resulting from inappropriate activation of the xcex11-adrenergic receptor.